The role of the androgens in the process of car-cinogenesis to prostate cancer has been hypothesized and examined in many studies. Given that exogenous androgens can initiate and/or promote prostate cancer in rodents and humans and that eunuchs rarely develop prostate cancer,58-61 circumstantial evidence implicates androgen levels in the etiology of prostate cancer. Further, a reduced risk of prostate cancer has been associated with certain hyperestrogenic-hypoandrogenic states,62 and estrogen therapy has a palliative effect in advanced cases.61 However, studies comparing hormone levels in men with and without prostate cancer have produced widely varying results.63,64 Several possibilities may explain these variations: small sample sizes, analyses of hormone levels in blood collected after the diagnosis of cancer, nonrepresentative control subjects, no adjustment for other related hormone levels and hormone-binding protein levels, and no adjustment for other potential confounding factors such as obesity. To date, one of the largest and most extensive case-control studies in this area was a prospective nested study done by Gann et al.65 to investigate sex hormone levels and the risk of prostate cancer. No clear association was found between the risk of prostate cancer and either unadjusted levels of sex hormones or sex hormone-binding globulin (SHBG). However, positive results were observed when hormone and SHBG levels were adjusted simultaneously. Specifically, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (95% CI 1.34-5.02, p = 0.004), and an inverse trend in risk was observed with increasing levels of both estradiol (95% CI 0.32-0.98, p = 0.03) and SHBG (95% CI 0.24-0.89, p = 0.01). The meta-analysis of Shaneyfelt et al.66 further confirmed the association of serum testosterone and SHBG levels with the risk of prostate cancer. The meta-analysis included three prospective cohort studies with data on all three sex hormones of interest.65,67,68 After multivariate adjustment, including the levels of other hormones, age, and body mass index, men with total serum testosterone in the highest quar-tile were 2.34 times more likely to develop prostate cancer (95% CI 1.30-4.20). Men with the highest SHBG levels were less likely to develop prostate cancer compared to those with the lowest SHBG levels (OR 0.46, 95% CI 0.240.89). These studies provide us with strong evidence that androgen and estrogen levels can alter an individuals' risk of prostate cancer.
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